Preparation process of glycyl-L-tyrosine

A preparation process, tyrosine technology, applied in the field of medicinal chemistry, can solve the problems of long synthetic route, reduce the total yield of aminoacyl-L-tyrosine, etc., reduce the reaction cost, reduce the difficulty of purification, and increase the yield and the effect of purity

Active Publication Date: 2013-03-27
SHANDONG QIDU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are mainly two ways to prepare glycyl-L-tyrosine: one is to condense L-tyrosine with chloroacetyl chloride and then prepare glycyl-L-tyrosine by ammonolysis. The starting raw materials of chloroacetyl chloride, L-tyrosine and ammonia water are all common raw materials, which are cheap and easy to get, and the reaction route is relatively short, which can greatly reduce the cost of the final product, and is more suitable for industrial production; the other is L -Tyrosine ester and N-protected glycine are used as starting materials for condensation synthesis of peptides to prepare glycyl-L-tyrosine. Compared with the first route, this route has a longer synthetic route and the synthesis of active esters And the removal step of protecting group reduces the total yield of aminoacyl-L-tyrosine synthesis

Method used

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  • Preparation process of glycyl-L-tyrosine
  • Preparation process of glycyl-L-tyrosine
  • Preparation process of glycyl-L-tyrosine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Add 200ml of concentrated ammonia water to a 250ml single-necked bottle, then add 10g of N-chloroacetyl-L-tyrosine, the solution is heated to 30°C with stirring, and the ammonia is decomposed for about 8 hours. 254 Plate, developer: chloroform-methanol (1:3), reaction product glycyl-L-tyrosine Rf value: about 0.3) monitor the reaction progress, when the L-tyrosine spot in the solution basically disappears, stop reaction. First, remove the ammonia gas at 40°C, -0.09±0.01Mpa, then distill the water to dryness under reduced pressure at 45°C, -0.09±0.01Mpa, add 10ml of purified water until the residue dissolves, and place the solution in Place in the refrigerator overnight for complete crystallization. After filtration, 8.8 g of crude product was obtained, with a yield of 82.3%. The HPLC purity is 98.25%, and the HPLC spectrum is shown in figure 1 , and the HPLC integration results are shown in Table 1.

[0040] The HPLC integral result table of table 1 embodiment 1

...

Embodiment 2

[0043] Add 7.0g of crude glycyl-L-tyrosine and 35ml of purified water into a 250ml single-necked bottle, then slowly heat to 50°C under stirring conditions, at this time the solids are all dissolved, then add 0.14g of activated carbon and stir After 40 minutes, filter while it is hot, continue to add 0.14g of activated carbon to the filtrate, stir at 50°C for 40 minutes, and then filter while it is hot. After the filtrate is slowly cooled to 25±2°C, add 35ml of ethanol dropwise. After the dropwise addition, place it in a Crystallize at -2±2°C for 8 hours to obtain 6.2g of refined glycyl-L-tyrosine with a yield of 88.6% and a HPLC purity of 99.65%. The HPLC spectrum is shown in figure 2 , and the HPLC integration results are shown in Table 2.

[0044] The HPLC integral result table of table 2 embodiment 2

[0045]

Embodiment 3

[0047] Add 150ml of concentrated ammonia water to a 250ml single-mouth bottle, then add 10g of N-chloroacetyl-L-tyrosine, the solution is heated to 35°C under stirring, and the ammonia is decomposed for about 10 hours. 254Plate, developer: chloroform-methanol (1:3), reaction product glycyl-L-tyrosine Rf value: about 0.3) monitor the reaction progress, when the L-tyrosine spot in the solution basically disappears, stop reaction. First, remove the ammonia gas at 40°C, -0.09±0.01Mpa, then distill the water to dryness under reduced pressure at 48°C, -0.09±0.01Mpa, add 20ml of purified water until the residue dissolves, and place the solution in Place in the refrigerator overnight for complete crystallization. After filtration, the crude product was 8.6g, and the yield was 80.7%. The HPLC purity is 98.62%, and the HPLC spectrum is shown in image 3 , and the HPLC integration results are shown in Table 3.

[0048] The HPLC integral result table of table 3 embodiment 3

[0049] ...

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Abstract

The invention discloses a preparation process of glycyl-L-tyrosine, and belongs to the field of pharmaceutical chemistry. The process comprises a condensation reaction and an ammonolysis reaction. In the ammonolysis reaction, N-chloroacetyl-L-tyrosine and concentrated aqueous ammonia are directly subjected to the ammonolysis reaction. When the reaction is finished, excessive aqueous ammonia is removed by reduced-pressure distillation under a temperature of 40-50 DEG C and a pressure of -0.08MPa to -0.10MPa. Residual substances are re-crystallized by using water, and the material is filtered, such that a glycyl-L-tyrosine crude product is obtained. In the ammonolysis step, N-chloroacetyl-L-tyrosine and concentrated aqueous ammonia are directly subjected to the reaction, and catalyzing of additional ammonium bicarbonate is not needed, such that glycyl-L-tyrosine purification difficulty is greatly reduced. Therefore, a problem of ammonium chloride removing difficulty caused by pH value regulation by using hydrochloric acid in post treatment can be avoided. Also, water re-crystallization is used for replacing WA-30 column chromatographic separation, such that product yield and purity are improved, and reaction cost is reduced. Obtained crude product can reach a medicinal grade through one-time refining, such that operation is greatly simplified, and industrialized production is facilitated.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation process of glycyl-L-tyrosine. Background technique [0002] Glycyl-L-tyrosine is a synthetic dipeptide formed by the reaction of tyrosine and glycine. At present, there are mainly two ways to prepare glycyl-L-tyrosine: one is to condense L-tyrosine with chloroacetyl chloride and then prepare glycyl-L-tyrosine by ammonolysis. The starting raw materials of chloroacetyl chloride, L-tyrosine and ammonia water are all common raw materials, which are cheap and easy to get, and the reaction route is relatively short, which can greatly reduce the cost of the final product, and is more suitable for industrial production; the other is L -Tyrosine ester and N-protected glycine are used as starting materials for condensation synthesis of peptides to prepare glycyl-L-tyrosine. Compared with the first route, this route has a longer synthetic route and the synthesis of active este...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K1/14
Inventor 郑家晴刘淑桂冯波张建礼崔美兰李洁周海洋刘明明刘淑静刘杰牛海岗
Owner SHANDONG QIDU PHARMA
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